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WO1993025553A1 - Oximes a substitution pyridino, pyrrolidino et azepino, utilisees comme agents anti-atherosclerotiques et anti-hypercholesterolemiques - Google Patents

Oximes a substitution pyridino, pyrrolidino et azepino, utilisees comme agents anti-atherosclerotiques et anti-hypercholesterolemiques Download PDF

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Publication number
WO1993025553A1
WO1993025553A1 PCT/US1993/004059 US9304059W WO9325553A1 WO 1993025553 A1 WO1993025553 A1 WO 1993025553A1 US 9304059 W US9304059 W US 9304059W WO 9325553 A1 WO9325553 A1 WO 9325553A1
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WIPO (PCT)
Prior art keywords
ethanone
oxime
pyridin
alkyl
methylimidazo
Prior art date
Application number
PCT/US1993/004059
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English (en)
Inventor
Scott D. Larsen
Charles H. Spilman
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The Upjohn Company
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Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Priority to DK93912362T priority Critical patent/DK0649425T3/da
Priority to DE69323883T priority patent/DE69323883T2/de
Priority to AU42933/93A priority patent/AU4293393A/en
Priority to EP93912362A priority patent/EP0649425B1/fr
Priority to JP6501458A priority patent/JPH07507796A/ja
Publication of WO1993025553A1 publication Critical patent/WO1993025553A1/fr
Priority to US08/313,684 priority patent/US5565468A/en
Priority to US08/468,158 priority patent/US5597816A/en
Priority to GR990401036T priority patent/GR3029946T3/el

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si

Definitions

  • the present invention relates to imidazopyridino-, pyrazolopyridino-, pyrazolapyrrolidino- and pyrozoloazepino-substituted oximes, useful for the treatment of atherosclerosis and hypercholesterolemia.
  • Atherosclerosis is a major cause of morbidity and mortality in the United States and Western European countries.
  • Hypercholesterolemia especially increased levels of low density lipoprotein (LDL) cholesterol, has been shown to be related to an increased risk of coronary heart disease (CHD) (Lowering blood cholesterol to prevent heart disease: NIH consensus development conference statement. (1985) Arteriosclerosis 5: 404-412).
  • CHD coronary heart disease
  • Arteriosclerosis 5: 404-412 Arteriosclerosis 5: 404-4112.
  • hypercholesterolemia contributes to 1.5 million myocardial infarctions per year and up to 0.5 million people die as a direct result of atherosclerotic cardiovascular disease (Lipid Research Clinics Program. The Lipid Research Clinics primary prevention trial results: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. (1984) JAMA 251: 365-
  • NCEP National Cholesterol Education Program
  • R is selected from the group consisting of
  • R 4 can be -(CH 2 ) b - or -(CH) 4 - which together with two adjacent carbons on the ring to which it is attached form an additional ring;
  • R 5 is -(CH 2 )
  • c 1-6;
  • phenyl-X is phenyl substituted by 1 to 3 same or different substituent selected from the group
  • the compounds of this invention may be supplied in capsules, tablets, suppositories, powders, or as fluid solutions and/or suspensions in aqueous or non- aqueous vehicles or can be added to food.
  • the compounds can be administered orally, intravenously, intramuscularly, intra-arterially, intraperitoneally, subcutaneously, sublingually, bucally to man or to other animals.
  • the dosage of each of the uses is about 0.1-200 mg kg.
  • the dosage will vary with the route of administration and the physical state of the recipient. Also, for example, the dosage by the oral route will depend on the frequency of administration and the weight of the recipient.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C r C j ) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • (C r C 8 )alkyl refers to alkyl of one to eight carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof.
  • phenyl-X examples include phenyl, (o-, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(o-, m-, or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4- 2,3,6-, or 2,4,5-)- trimethylphenyl, (o-, m-, or p-)fluorophenyl, (o-, m-, or p-trifluoromethyl)phenyl, 4- fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4, or 3,5-)difluor
  • Halogen is fluoro, chloro, bromo, or iodo or trifluoromethyl. It will be apparent to those skilled in the art that the oximes of this invention or their derivative may be syji or anti or mixtures thereof.
  • the scope of this invention includes all enantiomeric or diastereomeric forms of Formula I compounds either in pure form or as mixtures of enantiomers or diastereomers. The therapeutic properties of the compounds may to a greater or lesser degree depend on the stereochemistry of a particular compound. Pure enantiomers as well as enantiomeric or diastereomeric mixtures are within the scope of the invention.
  • Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate
  • step 1 A-l is reacted with 2,4-6-tri-t-butylphenol in the presence of potassium ferricyanide to yield A-2.
  • step 2 A-2 is reacted with hydroxylamine hydrochloride to yield A-3.
  • step 3 A-3 is reacted with n-butyl lithium and then with a source of electrophile E + such as diphenyldisulfide or methyliodide, to yield A-4. This procedure is discussed in Dimroth, K.; Tunscher, W. Synthesis 1977, 339.
  • step 1 B-l is either reacted with a substituted acetylene or heated with an olefin to yield B-2.
  • step 2 B-2 is reacted with hydroxylamine hydrochloride to yield B-3.
  • This procedure is based upon the procedure of Ranganathan, D.; Bamezai, S. Syn. Comm. 1985, 15, 259. Huisgen, R.; Grashey, R.; Gotthardt, H.; Schmidt, R. Ang. Chem. Int. Ed. 1962, 1, 48. Huisgen, R.; Gotthardt, H., Grashey, R. Chem. Ber. 1968, 101, 536. Hammick, D.L.; Voaden, D.J. J. Chem. Soc. 1961, 3303. Ranganathan, D.; Bamezai, S. Tet. Lett. 1983, 24, 1067. Scheme C
  • step 1 C-l is reacted with acetyl chicle to yield C-2.
  • step 2 C-2 is reacted with hydroxylamine hydrochloride to yield C-3.
  • This procedure is based upon the procedure of Potts, K.T.; Singh, U.P.; Bhattacharyya, J. J. Org. Chem. 1968, 33, 3766, Potts, K.T.; Dugas, R.; Surapaneni, C.R. J. Het. Chem. 1973, 10, 821.
  • step 1 aminopyridine D-1 is reacted with 3-chloro-2,4-pentanedione to form D-2.
  • step 2 D-2 is reacted with hydroxylamine hydrochloride to form D-3.
  • step 1 E-l (D-2) is reduced to form E-2.
  • step 2 is conducted in the same manner as step 2 of Scheme D to yield E-3.
  • the synthesis of E-l is based on the procedures of Schilling et al; Chem. Ber., 1955, 88, 1093; and Mosby et al; "Heterocyclic Systems with Bridgehead Nitrogen Atoms Pt. 1 "; Interscience; 1961, 462.
  • step 1 2-(aminomethyl)pyridine F-l is reacted with acetic anhydride to yield F-2.
  • step 2 F-2 is reacted with hydroxylamine hydrochloride to yield F-3.
  • This procedure is based upon the procedure described by Bower et al; J. Chem. Soc, 1955, 2834.
  • the two compounds were separated by flash chromatography (60% ethyl acetate/hexane, 300 g silica) to produce 2.62 g (65%) of Ethane, 1 -(4,5,6,7- tetrahydro-2-methylpyrazolo[l,5-a]-pyridin-3-yl)- of as yellow crystals.
  • An analytical sample was prepared by recrystallization from refluxing hexane (m.p. 67-69°C).
  • the reaction mixture was extracted with boiling hexane (14 x 25 mL) and the extracts cooled overnight to afford white needles which were mostly Ethanone, l-(4,5,6,7-tetrahydro-2- phenylpyrazolo[l,5-a]pyridin-3-yl)-.
  • the product was further purified by flash chromatography (100 g silica, 30% ethyl acetate hexane) to produce 2.82 g (56%) of the title compound as the major isomer (m.p. 111-113°C).
  • Hydroxylamine hydrochloride (20.85 g, 0.30 mole) and Ethanone, l-(5,6,7,8- tetrahydro-2-methyl-4H-pyrazolo[l,5-a]-azepin-3-yl)- (48.0 g, 0.25 mole) were stirred in a refluxing solution of ethanol (450 mL) and pyridine (150 mL) for 22 hrs. Solvent was removed in vacuo, leaving a thick slurry. Water (150 mL) was added, and the mixture was extracted with methylene chloride (1 x 250 mL, 1 x 100 mL). The organics were washed with brine (50 mL) and dried over magnesium sulfate.
  • Example 4 Ethanone, 1 -(4,5,6,7-tettahvdro-2-phenylpyrazolo[ 1 ,5-alpyridin-3-yl)-, oxime (A-3, Scheme A) Ethanone, l-(4,5,6,7-tetrahydro-2-phenylpyrazolo[l,5-a]pyridin-3-yl)- (2.27 g, 9.45 mmole) and hydroxylamine hydrochloride (788 mg, 11.34 mmole) were refluxed in absolute ethanol (17 mL) and pyridine (6 mL) for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with methylene chloride (4 x 50 mL).
  • Ethanone, l-(5,6-dihydro-2-methyl-4H-pyrrolo[l,2-b]pyrazol-3-yl)- (1.60 9, 9.74 mmole) and hydroxylamine hydrochloride (6.72 g, 97.4 mmole) were refluxed in absolute ethanol (94 mL) and pyridine (31 mL) for 6.5 hours.
  • Example 11 Ethanone, l-(2-methylimidazori,2-alpyridin-3-yl), oxime (D-3, Scheme D)
  • Ethanone, l-(2-methylimidazo[l,2-a]pyridin-3-yl)- (3.6 g, 20.6 mmole) and hydroxylamine hydrochloride (1.7 g, 24.7 mmole) were refluxed in absolute ethanol (41 mL) and pyridine (14 mL) for 16 hours. Water (150 mL) was added to the cooled solution and the white solid that precipitated was collected by filtration. The filtrate was extracted with chloroform (8 x 100 mL) and ethyl acetate (2 x 100 mL).
  • Ethanone, l-(2-methyl-5-phenylpyrazolo[l,5-a]pyridin-3-yl)- (10 g, 40 mmole) and hydroxylamine hydrochloride (3.5 g, 52 mmole) were refluxed in absolute ethanol (64 mL) and pyridine (35 mL) for 23.5 hours.
  • the cooled reaction mixture was diluted with water (200 mL) and extracted with methylene chloride (3 x 200 mL).
  • Acetamide, N-(3-acetyl-2-methylimidazo[l,2-a]pyridin-8-yl)- (4.6 g, 19.9 mmole), hydroxylamine hydrochloride (1.8 g, 25.9 mmole) and sodium acetate (2.0 g) were refluxed in absolute ethanol (40 mL) for 5.5 hours.
  • the cooled reaction mixture was diluted with water (250 mL) and the resulting solid was collected by filtration.
  • the filtrate was extracted with methylene chloride (2 x 250 mL) and the organic layers were dried over magnesium sulfate and concentrated to produce a yellow oil.
  • the oil and the solid were combined and dissolved in refluxing 95% ethanol (325 mL) and water (160 mL) to produce 2.10 g (43%) of the title compound as off-white crystals upon cooling (280-281°C, dec).
  • Methanone, (2-methylimidazo[l,2-a]pyridin-3-yl)phenyl- (9.0 g, 38 mmole) and hydroxylamine hydrochloride (4.0 g, 57 mmole) were refluxed in absolute ethanol (76 mL) and pyridine (38 mL) for 24 hours.
  • the cooled reaction mixture was diluted with water (500 mL) and the resulting solid was collected by filtration.
  • the filtrate was extracted with methylene chloride (4 x 500 mL) and the organic layers were dried over magnesium sulfate and concentrated to produce a yellow solid.
  • the cooled reaction mixture was diluted with water (200 mL) and extracted with methylene chloride (4 x 200 mL). The organic layers were dried over magnesium sulfate and concentrated to produce a white solid which was dissolved in refluxing 95% ethanol (100 mL) and water (125 mL) to produce 2.54 g (81%) of white crystals upon cooling.
  • This material contained a 1.9:1 ratio of oxime isomers (m.p. 209-210°C) with the title compound being the major isomer.
  • An analytical sample could be obtained by recrystallization from refluxing ethyl acetate and petroleum ether (1:1 ratio) to produce a 2.8:1 ratio of oxime isomers as white crystals (m.p. 188-190°C dec.) with the title compound being the major isomer.
  • Example 32 Ethanone, l-(2-methylimidazoll,2-alpyridin-3-yl)-acetyl hvdrazone l-(2-methylimidazo[l,2-a]pyridin-3-yl)- Ethanone, (32 g, 0.183 mole) and acetic hydrazide (68 g, 0.918 mole) were refluxed in THF (120 mL and acetic acid (1.1 mL) for 10 days. The cooled reaction mixture was filtered and the filtrate diluted with methylene chloride (500 mL) and washed with water (3 x 500 mL).
  • the aqueous phase was made basic with solid potassium hydroxide, the solution was filtered and the filtrate extracted with chloroform (3 x 500 mL).
  • the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to produce a yellow solid which was dissolved in refluxing methylene chloride (350 mL) and hexane (50 mL) and cooled at 0°C for 1.5 hours to produce a white solid upon cooling. Subsequent recrystallizations produced a total of 7.50 g (17%) of white crystals as a mixture of isomers (m.p. 196- 198°C).
  • the compounds of this invention are useful for the treatment of atherosclerosis and hypochlosterolemia. These utilities of the compounds are shown by the following test. I. Anti-Atherosclerotic Activity
  • ⁇ - and ⁇ - lipoproteins were isolated from individual serum samples by precipitation using PEG-8000. Cholesterol concentrations in the ⁇ - and ⁇ - lipoprotein fractions were measured using a Demand autoanalyzer and Demand enzymatic reagents. All data were analyzed using a one-way classification design after transforming the data to logarithms to achieve more homogeneous within-group variances. Table 1; Serum Cholesterol Data (LDL + VLDL) for Selected Compounds of the Invention. Data from Chow-Fed Quail. Compound Number LDL + VLDL Cholesterol T/C
  • Tables 1 and 2 show results for those compounds which have been tested in chow-fed quail or cholesterol-fed quail, respectively, for their ability to reduce serum cholesterol levels. A ratio of drug treated/control (T/C) serum cholesterol levels of 0.85 or less was considered active.
  • the compound Ethanone, l-(3-methylimidazo[l,5-a]pyridin-l-yl)-,oxime and its use in the treatment of atherosclerosis and hypercholesterolemia is contemplated as the best mode of practicing this invention.

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Abstract

Oximes à substitution imidazopyridino, pyrazolopyridino, pyrazolapyrralidino et pyrozoloazépino, ayant les formules (I), (II), (III), (IV) et (V), dans lesquelles R?1, R2, R3, R4, R5¿ et a sont tels que décrits dans les revendications. Ces composés sont utiles dans le traitement de l'athérosclérose et de l'hypercholestérolémie.
PCT/US1993/004059 1992-06-17 1993-05-05 Oximes a substitution pyridino, pyrrolidino et azepino, utilisees comme agents anti-atherosclerotiques et anti-hypercholesterolemiques WO1993025553A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DK93912362T DK0649425T3 (da) 1992-06-17 1993-05-05 Pyridino-, pyrrolidino- og azepino-substituerede oximer, som er anvendelige som anti-atherosklerose- og anti-hypercholester
DE69323883T DE69323883T2 (de) 1992-06-17 1993-05-05 Pyrridino-, pyrrolidino- und azepino-substituierte oxime als antiatherosklerosemittel und antihypercholesterolemiemittel
AU42933/93A AU4293393A (en) 1992-06-17 1993-05-05 Pyridino-, pyrrolidino- and azepino-substituted oximes useful as anti-atherosclerosis and anti-hypercholesterolemic agents
EP93912362A EP0649425B1 (fr) 1992-06-17 1993-05-05 Oximes a substitution pyridino, pyrrolidino et azepino, utilisees comme agents anti-atherosclerotiques et anti-hypercholesterolemiques
JP6501458A JPH07507796A (ja) 1992-06-17 1993-05-05 抗−アテローム性動脈硬化剤および抗−高コレステロール血症剤として有用なピリジノ−，ピロリジノ−，およびアゼピノ−置換オキシム類
US08/313,684 US5565468A (en) 1992-06-17 1994-09-27 Pyridino substituted oximes useful as anti-atherosclerosis and anti-hypercholesterolemic agents
US08/468,158 US5597816A (en) 1992-06-17 1995-06-06 Pyrazoloazepino substituted oximes useful as anti-atherosclerosis and anti-hypercholesterolemic agents
GR990401036T GR3029946T3 (en) 1992-06-17 1999-04-13 Pyridino-, pyrrolidino- and azepino-substituted oximes useful as anti-atherosclerosis and anti-hypercholesterolemic agents.

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US90022992A 1992-06-17 1992-06-17
US07/900,229 1992-06-17

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US (3) US5565468A (fr)
EP (1) EP0649425B1 (fr)
JP (1) JPH07507796A (fr)
CN (1) CN1081678A (fr)
AT (1) ATE177426T1 (fr)
AU (1) AU4293393A (fr)
DE (1) DE69323883T2 (fr)
DK (1) DK0649425T3 (fr)
ES (1) ES2130269T3 (fr)
GR (1) GR3029946T3 (fr)
IL (1) IL105693A0 (fr)
MX (1) MX9303594A (fr)
WO (1) WO1993025553A1 (fr)

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US7501438B2 (en) 2006-07-07 2009-03-10 Forest Laboratories Holdings Limited Pyridoimidazole derivatives
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
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US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
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US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
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WO2004037822A1 (fr) * 2002-10-22 2004-05-06 Eisai Co., Ltd. Composes de 7-phenyle pyrazolopyridine
US7176216B2 (en) * 2002-10-22 2007-02-13 Eisai Co., Ltd. 7-phenylpyrazolopyridine compounds
EP2176260A1 (fr) * 2007-07-11 2010-04-21 Auckland Uniservices Limited Pyrazolo[1,5-a]pyridines et leur utilisation en cancérothérapie
BRPI0911659B8 (pt) * 2008-04-15 2021-05-25 Eisai R&D Man Co Ltd composto 3-fenilpirazolo[5,1-b]tiazol e composição farmacêutica compreendendo o mesmo
WO2011043387A1 (fr) * 2009-10-08 2011-04-14 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de pyrazolooxazole
AR078521A1 (es) * 2009-10-08 2011-11-16 Eisai R&D Man Co Ltd Compuesto pirazolotiazol
CN103980281B (zh) * 2014-05-27 2016-06-08 天津市斯芬克司药物研发有限公司 一种咪唑吡嗪化合物及其制备方法

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EP0007678A1 (fr) * 1978-07-25 1980-02-06 Acf Chemiefarma Nv Ethers d'oxime, leur préparation et compositions pharmaceutiques les contenant
EP0299209A2 (fr) * 1987-06-15 1989-01-18 Fujisawa Pharmaceutical Co., Ltd. Composés de pyrazolopyridine et procédés pour leur préparation

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Publication number Publication date
DK0649425T3 (da) 1999-09-27
EP0649425B1 (fr) 1999-03-10
CN1081678A (zh) 1994-02-09
JPH07507796A (ja) 1995-08-31
DE69323883T2 (de) 1999-07-22
ATE177426T1 (de) 1999-03-15
IL105693A0 (en) 1993-09-22
US5597816A (en) 1997-01-28
US5565468A (en) 1996-10-15
GR3029946T3 (en) 1999-07-30
MX9303594A (es) 1994-01-31
ES2130269T3 (es) 1999-07-01
DE69323883D1 (de) 1999-04-15
US5523318A (en) 1996-06-04
AU4293393A (en) 1994-01-04
EP0649425A1 (fr) 1995-04-26

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